AChEi Brief: Reference Abstracts



Acetylcholinesterase Inhibitor Brief: Reference Abstracts

1. Fricker, R.D., et al., A Review of the Scientific Literature as It Pertains to Gulf War Illnesses. Volume 12: Pesticide Use During the Gulf War: A Survey of Gulf War Veterans. 2000, Santa Monica, CA: RAND, MR-1018/12-OSD.

2. Golomb, B.A., Illness in Persian Gulf War veterans: Evidence for a causal role for acetylcholinesterase inhibitors (pyridostigmine bromide, pesticides, and nerve agent). Submitted.

3. Nisenbaum, R., et al., Deployment stressors and a chronic multisymptom illness among Gulf War veterans. J Nerv Ment Dis, 2000. 188(5): p. 259-66. Unusual health problems have been reported by Gulf War (GW) veterans, but no single etiology has been linked to these illnesses. This study was conducted to determine the association between self-reported GW deployment stressors and an illness defined by a combination of fatigue, mood-cognition, and musculoskeletal symptoms. A total of 1002 GW veterans from this cross-sectional survey of four Air Force units completed a self-administered questionnaire that asked about symptoms, demographic and military characteristics, and stressors during deployment. Severe and mild-moderate illness was positively associated with self-reports of pyridostigmine bromide use, insect repellent use and belief in a threat from biological or chemical weapons. Injuries requiring medical attention were only associated with severe illness. These results suggest a link between self-reported chemical, emotional, and physical exposures, and GW veterans' illness. Further research is needed to determine physiological and psychological mechanisms through which such stressors could have contributed to this symptom complex.

4. Unwin, C., et al., Health of UK servicemen who served in the Persian Gulf war. Lancet, 1999. 353: p. 169-178. BACKGROUND: Various symptoms in military personnel in the Persian Gulf War 1990-91 have caused international speculation and concern. We investigated UK servicemen. METHODS: We did a cross-sectional postal survey on a random sample of Gulf War veterans (Gulf War cohort, n=4248) and, stratified for age and rank, servicemen deployed to the Bosnia conflict (Bosnia cohort, n=4250) and those serving during the Gulf War but not deployed there (Era cohort, n=4246). We asked about deployment, exposures, symptoms, and illnesses. We analysed men only. Our outcome measures were physical health, functional capacity (SF-36), the general health questionnaire, the Centers for Disease Control and Prevention (CDC) multisymptom criteria for Gulf War illness, and post-traumatic stress reactions. FINDINGS: There were 8195 (65.1%) valid responses. The Gulf War cohort reported symptoms and disorders significantly more frequently than those in the Bosnia and Era cohorts, which were similar. Perception of physical health and ability were significantly worse in the Gulf War cohort than in the other cohorts, even after adjustment for confounders. Gulf War veterans were more likely than the Bosnia cohort to have substantial fatigue (odds ratio 2.2 [95% CI 1.9-2.6]), symptoms of post-traumatic stress (2.6 [1.9-3.4]), and psychological distress (1.6 [1.4-1.8]), and were nearly twice as likely to reach the CDC case definition (2.5 [2.2-2.8]). In the Gulf War, Bosnia, and Era cohorts, respectively, 61.9%, 36.8%, and 36.4% met the CDC criteria, which fell to 25.3%, 11.8%, and 12.2% for severe symptoms. Potentially harmful exposures were reported most frequently by the Gulf War cohort. All exposures showed associations with all of the outcome measures in the three cohorts. Exposures specific to the Gulf were associated with all outcomes. Vaccination against biological warfare and multiple routine vaccinations were associated with the CDC multisymptom syndrome in the Gulf War cohort. INTERPRETATION: Service in the Gulf War was associated with various health problems over and above those associated with deployment to an unfamiliar hostile environment. Since associations of ill health with adverse events and exposures were found in all cohorts, however, they may not be unique and causally implicated in Gulf-War-related illness. A specific mechanism may link vaccination against biological warfare agents and later ill health, but the risks of illness must be considered against the protection of servicemen.

5. Golomb, B.A., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 2: Pyridostigmine Bromide. 1999, Santa Monica, CA: RAND. 385.

6. Cecchine, G., et al., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 8: Pesticides. 2000, Santa Monica, CA: RAND. 182.

7. Li, L., et al., Reactive oxygen species mediate pyridostigmine-induced neuronal apoptosis: involvement of muscarinic and NMDA receptors. Toxicol Appl Pharmacol, 2001. 177(1): p. 17-25. Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor used for treatment of myasthenia gravis and for prophylactic protection against organophosphate nerve agent. We previously showed PB can induce apoptotic death in rat brain following systemic treatment. To study mechanisms by which PB induces brain cell death, cultured rat cerebellar granule cells were used. Cytotoxicity was determined after exposure to PB (10-1000 microM) for 24 h; a high concentration of PB (>500 microM) significantly increased lactate dehydrogenase release, which was reduced by pretreatment with the antioxidant, N-t-butyl-alpha-phenyl-nitrone (PBN). Apoptosis, as determined by TUNEL staining, was concentration dependent (10-250 microM) after a 24-h exposure and cytotoxicity was confirmed by gel electrophoresis of DNA, release of cytochrome c from mitochondria, elevation of caspase activity, and electron microscopy. The oxidant-sensitive fluorescent dye 2',7'-dichlorofluorescin diacetate was used to detect reactive oxidative species (ROS) generation. Pretreatment with PBN, superoxide dismutase, catalase, or the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) blocked PB-induced ROS generation and apoptotic cell death. Pretreatment with atropine or MK-801 blocked ROS generation and the subsequent neurotoxicity, showing that both muscarinic and NMDA receptors mediate the response. DNA extracted from PB-treated cells revealed oligonucleosomal fragmentation on gel electrophoresis and antioxidants attenuated the DNA fragmentation, providing further evidence for a link of ROS generation and apoptosis. These results indicate that muscarinic receptor-mediated ROS generation is an initiating factor in PB-induced apoptotic cell death and activation of the NMDA glutamate receptor is directly linked to the response.

8. Li, L., et al., Muscarinic receptor-mediated pyridostigmine-induced neuronal apoptosis. Neurotoxicology, 2000. 21(4): p. 541-552. Abstract: Pyridostigmine is a reversible cholinesterase (ChE) inhibitor that is associate with neurologic dysfunction involving both central and peripheral nervous systems. To determine the neurotoxic potential of pyridostigmine, rats were sacrificed at intervals after drug administration (0.5-1.85 mg/kg, i.p., twice daily for 4 days) and brains examined histologically. ChE inhibition was used as a biomarker of pyridostigmine activity. Using the in situ terminal deoxynucleotidyl transferase nick-end labeling of DNA fragments (TUNEL) method and electron microscopy, apoptotic brain cell death was noted in cerebral cortex over a dose range of 0.5-1.85 mg/kg and at the higher dose (1.85 mg/kg), apoptosis was also noted in striatum and hippocampus. These responses were blocked by pretreatment with atropine. Rat cortical cells in culture also underwent apoptosis when exposed to pyridostigmine (250 microM for 24 hr), indicating that the pyridostigmine can initiate apoptosis, independent of peripheral mechanisms. Pretreatment of cells with atropine (10 microM) inhibited pyridostigmine-induced apoptosis, confirming the response was mediated by muscarinic receptors. Short term treatment of rats with pyridostigmine (1.85 mg/kg twice daily for 4 days) induced a prolonged apoptotic response, which was evident in rat cortex up to 30 days after the last dose. Active apoptosis persisted, despite recovery of serum ChE activity. These in vivo and in vitro observations indicate that pyridostigmine can initiate a prolonged neurodegeneration.

9. Pascuzzo, G.J., et al., The nature of the interactions of pyridostigmine with the nicotinic acetylcholine receptor-ionic channel complex I. Agonist, desensitizing, and binding properties. Mol Pharmacol, 1984. 25: p. 92-101.

10. Tandon, P., et al., Fenthion produces a persistent decrease in muscarinic receptor function in the adult rat retina. Toxicol Appl Pharmacol, 1994. 125: p. 271-280.

11. Tandon, P., et al., Dose-response study of the tissue-specific effects of fenthion on receptor function in rat CNS. Toxicologist, 1994. 14: p. 257.

12. Sherby, S.M., et al., Comparison of actions of carbamate anticholinesterses on the nicotinic acetylcholine receptor. Molecular Pharmacology, 1985. 27: p. 343-348.

13. Gupta, R.C., G.T. Patterson, and W.-D. Dettbarn, Mechanisms of toxicity and tolerance to diisopropylphosphorofluoridate at the neuromuscular junction of the rat. Toxicology and Applied Pharmacology, 1986. 84: p. 541-550.

14. Eskenazi, B., A. Bradman, and R. Castorina, Exposures of children to organophosphate pesticides and their potential adverse health effects. Environ Health Perspect, 1999. 107 Suppl 3: p. 409-19. Recent studies show that young children can be exposed to pesticides during normal oral exploration of their environment and their level of dermal contact with floors and other surfaces. Children living in agricultural areas may be exposed to higher pesticide levels than other children because of pesticides tracked into their homes by household members, by pesticide drift, by breast milk from their farmworker mother, or by playing in nearby fields. Nevertheless, few studies have assessed the extent of children's pesticide exposure, and no studies have examined whether there are adverse health effects of chronic exposure. There is substantial toxicologic evidence that repeated low-level exposure to organophosphate (OP) pesticides may affect neurodevelopment and growth in developing animals. For example, animal studies have reported neurobehavorial effects such as impairment on maze performance, locomotion, and balance in neonates exposed (italic)in utero(/italic) and during early postnatal life. Possible mechanisms for these effects include inhibition of brain acetylcholinesterase, downregulation of muscarinic receptors, decreased brain DNA synthesis, and reduced brain weight in offspring. Research findings also suggest that it is biologically plausible that OP exposure may be related to respiratory disease in children through dysregulation of the autonomic nervous system. The University of California Berkeley Center for Children's Environmental Health Research is working to build a community-university partnership to study the environmental health of rural children. This Center for the Health Assessment of Mothers and Children of Salinas, or CHAMACOS in Monterey County, California, will assess (italic)in utero(/italic) and postnatal OP pesticide exposure and the relationship of exposure to neurodevelopment, growth, and symptoms of respiratory illness in children. The ultimate goal of the center is to translate research findings into a reduction of children's exposure to pesticides and other environmental agents, and thereby reduce the incidence of environmentally related disease.

15. Costa, L.G., B.W. Schwab, and S.D. Murphy, Tolerance to anticholinesterase compounds in mammals. Toxicology, 1982. 25: p. 79-97.

16. Buccafusco, J.J., Chronic organophosphorus exposure and cognition. 1999 Annual Report to Congress on Gulf War Veterans' Illnesses, 2000: p. 101.

17. Lev-Lehman, E., et al., Synaptogenesis and myopathy under acetylcholinesterase overexpression. Journal of Molecular Neuroscience, 2000. 14(1-2): p. 93-105. Abstract: Environmental, congenital, and acquired immunological insults perturbing neuromuscular junction (NMJ) activity may induce a variety of debilitating neuromuscular pathologies. However, the molecular elements linking NMJ dysfunction to long-term myopathies are unknown. Here, we report dramatically elevated levels of mRNA encoding c-Fos and the "readthrough" (R) variant of acetylcholinesterase (AChE) in muscles of transgenic mice overexpressing synaptic (S) AChE in motoneurons and in control mice treated with the irreversible cholinesterase inhibitor diisopropylfluorophosphonate (DFP). Tongue muscles from DFP-treated and AChE-S transgenic mice displayed exaggerated neurite branching and disorganized, wasting fibers. Moreover, diaphragm muscles from both transgenic and DFP-treated mice exhibited NMJ proliferation. 2'-O-methyl-protected antisense oligonucleotides targeted to AChE mRNA suppressed feedback upregulation of AChE and ameliorated DFP-induced NMJ proliferation. Our findings demonstrate common transcriptional responses to cholinergic NMJ stress of diverse origin, and implicate deregulated AChE expression in excessive neurite outgrowth, uncontrolled synaptogenesis, and myopathology.

18. Robinson, D. and R. McGee, Agonist-induced regulation of neuronal nicotinic acetylcholine receptor of PC12 cells. Molecular Pharmacology, 1985. 27: p. 409-417.

19. Sherby, S.M., et al., Comparison of actions of carbamate anticholinesterses on the nicotinic acetylcholine receptor. Molecular Pharmacology, 1985. 27: p. 343-348.

20. Shaw, K.-P., et al., The reversible cholinesterase inhibitor physostgmine has channelblocking and agonist efects on the acetylcholine receptor-ion channel complex. Molecular Pharmacology, 1985. 28: p. 527-238.

21. Anderson, R.J., et al., Decreased tetanic contracture of rat skeletal muscle induced by pyridostigmine. J Toxicol Environ Health, 1986. 18: p. 221-230.

22. Haley, R.W., S. Billecke, and B.N. La Du, Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol, 1999. 157(3): p. 227-33. Previously Haley et al. described six possible syndromes identified by factor analysis of symptoms in Gulf War veterans and demonstrated that veterans with these symptom complexes were more neurologically impaired than age-sex-education-matched well controls. They also uncovered strong associations (relative risks 4-8) suggesting that these symptom complexes were related to wartime exposure to combinations of organophosphate pesticides, chemical nerve agents, high concentration DEET insect repellant, and symptoms of advanced acute toxicity after taking pyridostigmine. Here we have shown that compared to controls, ill veterans with the neurologic symptom complexes were more likely to have the R allele (heterozygous QR or homozygous R) than to be homozygous Q for the paraoxonase/arylesterase 1 (PON1) gene. Moreover, low activity of the PON1 type Q (Gln192, formerly designated type A) arylesterase allozyme distinguished ill veterans from controls better than just the PON1 genotype or the activity levels of the type R (Arg192, formerly designated type B) arylesterase allozyme, total arylesterase, total paraoxonase, or butyrylcholinesterase. A history of advanced acute toxicity after taking pyridostigmine was also correlated with low PON1 type Q arylesterase activity. Type Q is the allozyme of paraoxonase/arylesterase that most efficiently hydrolyzes several organophosphates including sarin, soman, and diazinon. These findings further support the proposal that neurologic symptoms in some Gulf War veterans were caused by environmental chemical exposures.

23. La Du, B.N., et al., Serum paraoxonase (PON1) isozymes: the quantitative analysis of isozymes affecting individual sensitivity to environmental chemicals. Drug Metab Dispos, 2001. 29(4 Pt 2): p. 566-9. In a recent study on Gulf War veterans who developed delayed neurotoxicity symptoms, we found their levels of serum paraoxonase (PON1) isozyme type Q to be significantly lower than in the control, unaffected veteran group. These results were obtained in 25 ill veterans and 20 well control subjects, of which 10 were deployed and 10 were nondeployed battalion members who remained in the United States during the Gulf War. The blood samples were also assayed for serum butyrylcholinesterase in our laboratory, and more recently in Dr. C. Broomfield's laboratory for somanase and sarinase activities. The cholinesterase activities showed no significant correlation with the PON1 isozyme levels or the severity of the clinical symptoms, but the somanase and sarinase levels ran parallel to the PON1 type Q isozyme concentrations. Although there is no direct evidence that these Gulf War veterans were directly exposed to or encountered either of these nerve gases, they may have been exposed to some environmental or chemical toxin with a similar preference for hydrolysis by the PON1 type Q isozyme. The number of subjects is relatively small, but the results should encourage other investigators to examine both the individual phenotypes and the levels of PON1 isozymes in other groups exhibiting neurological symptoms.

24. Mackness, B., P.N. Durrington, and M.I. Mackness, Low paraoxonase in Persian Gulf War Veterans self-reporting Gulf War Syndrome. Biochem Biophys Res Commun, 2000. 276(2): p. 729-33. Exposure to organophosphate (OP's) insecticides and nerve gases during the Persian Gulf War has been implicated in the development of Gulf War Syndrome. Paraoxonase (PON1) present in human serum detoxifies OP's. We determined the levels of PON1 in the serum of Gulf War Veterans and compared these to those found in a control population. One hundred fifty-two Gulf War Veterans from the UK who self-reported the presence of Gulf War Syndrome via a questionnaire and 152 age and gender matched controls were studied. PON1 activity, concentration, and genotype were determined. In the Gulf War Veterans, paraoxon hydrolysis was less than 50% of that found in the controls (100.3 (14.8-233.8) vs 214.6 (50.3-516.2) nmol/min/ml, P < 0.001). This low activity was independent of the effect of PON1 genotype. The serum PON1 concentration was also lower in the Gulf War Veterans (75.7 (18.1-351.3) vs 88.2 (34.5-527.4) microg/ml, P < 0.00025), which was again independent of PON1 genotype. There was no difference in the rate of diazoxon hydrolysis between the groups (10. 2 +/- 4.1 micromol/min/ml vs 9.86 +/- 4.4, P = NS). A decreased capacity to detoxify OP insecticides resulting from low serum PON1 activity may have contributed to the development of Gulf War Syndrome.

25. Cherry, N., et al., Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip. Lancet, 2002. 359(9308): p. 763-4. Human serum paraoxonase (PON1) hydrolyses diazinonoxon, the active metabolite of diazinon, which is an organophosphate used in sheep dip. In a case-referent study, 175 farmers with ill health that they attributed to sheep dip nominated 234 referent farmers who also dipped sheep and whom they believed to be in good health. We calculated odds ratios for polymorphisms in PON1 at positions 192 and 55, and for PON1 activity with diazinonoxon as substrate. Cases were more likely than referents to have at least one R allele at position 192 (glutamine to arginine aminoacid substitution; odds ratio 1center dot93, 95% CI 1center dot24--3center dot01), both alleles of type LL (1center dot70, 1center dot07--2center dot68) at position 55, and to have diazoxonase activity below normal median (1center dot77, 1center dot18--2center dot67). Our results support the hypothesis that organophosphates contribute to the reported ill health of people who dip sheep.

26. Cecchine, G., et al., A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 8: Pesticides. 2000, Washington, DC: RAND. 182.

27. Cherry, N., et al., Health and exposures of United Kingdom Gulf war veterans. Part II: The relation of health to exposure. Occup Environ Med, 2001. 58(5): p. 299-306. OBJECTIVES: To investigate whether, in personnel who served with the United Kingdom forces in the Gulf war, self reported exposures were related to symptoms in a way that was consistent, specific, and credible. METHODS: Responses to symptom and exposure questionnaires, completed 7 or more years after the war, were collected from 7971 subjects deployed in the Gulf, from two exposed cohorts, in a study with an overall response rate of 85.5%. Exposures were considered in three groups, those outside the control of the subjects, the use of prophylaxis, and indicators of susceptibility. Health indices derived from symptom questionnaires were related to reports of 14 exposures in these three groups in a series of multiple regression analyses to allow for confounding. The relation of exposure to complaints of widespread pain and to symptoms suggesting peripheral neuropathy were examined by logistic regression. RESULTS: Consistent but weak correlations between exposures and with health effects were found in independent analyses of the two (main and validation) cohorts. Three exposures outside the control of the subject, the number of inoculations, the number of days handling pesticides, and the days exposed to smoke from oil fires, were consistently and independently related to severity. The number of inoculations was also associated with higher scores on a factor weighted on symptoms associated with skin and musculoskeletal complaints. The number of days handling pesticides related particularly to scores on a neurological factor and to symptoms consistent with toxic neuropathy. CONCLUSION: The relations between exposures and ill health were generally weak. Consistent, specific, and credible relations, warranting further investigation, were found between health indices and two exposures, the reported number of inoculations and days handling pesticides.

28. Gray, G.C., et al., Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: the Seabee Health Study. Am J Epidemiol, 2002. 155(11): p. 1033-44. US Navy Seabees have been among the most symptomatic Gulf War veterans. Beginning in May 1997, the authors mailed Gulf War-era Seabees a health survey in serial mailings. As of July 1, 1999, 68.6% of 17,559 Seabees contacted had returned the questionnaire. Compared with other Seabees, Gulf War Seabees reported poorer general health, a higher prevalence of all 33 medical problems assessed, more cognition difficulties, and a higher prevalence of four physician-diagnosed multisymptom conditions: chronic fatigue syndrome, posttraumatic stress disorder, multiple chemical sensitivity, and irritable bowel syndrome. Because the four multisymptom conditions were highly associated with one another, the authors aggregated them into a working case definition of Gulf War illness. Among the 3,831 (22% cases) Gulf War Seabee participants, multivariable modeling revealed that female, Reserve, and enlisted personnel and participants belonging to either of two particular Seabee units were most likely to meet the case definition. Twelve of 34 self-reported Gulf War exposures were mildly associated with meeting the definition of Gulf War illness, with exposure to fumes from munitions having the highest odds ratio (odds ratio = 1.9, 95% confidence interval: 1.5, 2.4). While these data do not implicate a specific etiologic exposure, they demonstrate a strong association and a high prevalence of self-reported multisymptom conditions in a large group of symptomatic Gulf War veterans.

29. Haley, R.W. and T.L. Kurt, Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. Jama, 1997. 277(3): p. 231-7. OBJECTIVE: To identify risk factors of factor analysis-derived Gulf War-related syndromes. DESIGN: A cross-sectional survey. PARTICIPANTS: A total of 249 Gulf War veterans from the Twenty-fourth Reserve Naval Mobile Construction Battalion. DATA COLLECTION: Participants completed standardized booklets measuring self-reported wartime exposures and present symptoms. MAIN OUTCOME MEASURES: Associations of factor analysis-derived syndromes with risk factors for chemical interactions that inhibit butyrylcholinesterase and neuropathy target esterase. RESULTS: Risk of syndrome 1 ("impaired cognition") was greater in veterans who reported wearing flea collars during the war (5 of 20, 25%) than in those who never wore them (7 of 229, 3%; relative risk [RR], 8.7; 95% confidence interval [CI], 3.0-24.7; P ................
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